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Hi, folks! Well, just to inject some new food for thought, I'm posting some information that I haven't posted here before. If you'll remember from my original short synopsis of my research that Arron so graciously posted as an editorial on this website, I very quickly mentioned PTX3.

I thought you might be interested to see what I found when I looked up PTX3 further. I did it just as a quick curiosity thing. I sent this to the NMSS, also (as I do all my research compilations). As a matter of fact, here's a copy of my letters to the NMSS.

Here goes. This is REAL lengthy! I thought I'd warn you before you even get started. I've highlighted text, though, in case you want to bounce through it. My comments are in blue - mention of note in abstracts are in red.

Oh, please note that Dr. Sulser is the man who originally discovered/created desipramine (my MS drug of choice) way back in about the 60s, I believe. He is still alive and works..........ta da ...........as a laboratory department head at no other place than right here at Vanderbilt Medical Center. I was SHOCKED! HAH!

Deb

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Just to provide a little evidence for the "connection" that I touched upon in my original research paper regarding desipramine and PTX3, I thought I would show you how I got there. I usually work backwards when I research. I found Dr. Sulser's quick mention of IL1-b in connection with PTX3, and the implication for immunomodulation, so I thought......hmmmmmm...what's that all about? Hence, I went on from there.

We already know all the adverse implications of IL1-b and TNFa, etc., in inflammation, and their direct connection to MS. And I won't go back over the evidence of desipramine's direct regulation of IL1-b and TNFa, which appears more and more important in MS. I won't rehash all that. The PTX3 portion of the puzzle, though, got my attention for a bit. So far, (as far as I can find anyway), no MS researcher has touched upon this piece of the puzzle yet.

It's too early, of course, to tell exactly what and/or how desipramine will affect PTX3, etc., via what I call the trickle down effect, but based on all the additional chain-reaction effects of desipramine as pointed out in my original compilation, I believe we can safely and definitively say that desipramine is "regulatory" in its actions. And with MS, its all about improving the timing of or regulating the body's apoptosis processes, right? (Or at least that is the way I describe it. It's all in the "timing".)

As I just noted, though, a direct connection between PTX3 and MS cannot be made yet. PTX3 is still under intense scrutiny, because its "discovery" shall we say, is fairly new, so not much is really known yet. It's just a small piece of the pie, but still............very interesting..........

"....The results are consistent with the reported effects of IL-1beta on PTX3 expression in mouse brain. The results are of potential importance because PTX3 is a member of the long pentraxin subfamily of acute-phase proteins, which is inducible by IL-1beta, and may play roles in neuroimmunity and neuroprotection."

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So then I started to work backwards. If you notice the year of this next item, Sulser stumbled onto this quite some time ago. Here is where I picked up the Netherlands University's direct connection between beta adrenoceptors and norepinephrine to MS. I provided the missing link of testing the drug desipramine to see exactly how or whether it will help MS. (Hence back around in a circle to my original research compilation.)

Eur Arch Psychiatry Neurol Sci. 1989;238(5-6):231-9.

New perspectives on the molecular pharmacology of affective disorders.

Sulser F.

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.

"....The molecular neurobiology of beta adrenoceptors, with its implication for genetic and immunologic investigations, is briefly discussed and further research on stimulus-transcription coupling and regulation of gene expression in brain is suggested as an exciting new direction in central receptor research relevant to the psychopharmacology of affective and other disorders.

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The next connection between PTX3 and autoimmunity can be found in this article. It's too long to quote here, but I believe the title alone says it all. Consider this just a missing footnote, perhaps, to justify my earlier connections and hypotheses.

Blood, 15 December 2000, Vol. 96, No. 13, pp. 4300-4306

IMMUNOBIOLOGY

The Long Pentraxin PTX3 Binds to Apoptotic Cells and Regulates Their Clearance by Antigen-Presenting Dendritic Cells

I’m back to researching. This time on PTX3. This is sort of all over the board, as I say, and I’m a little off my usual course by getting into causal relationships, but that is where I accidentally ended up on this. I’m going back now and sticking with pharmacology and therapeutic applications for MS, and my original goal of getting desipramine looked at for MS therapy. What I’m about to show here, though, might represent a really unique NMSS funding opportunity for someone who makes application to research “PTX3 and its direct role in MS”. And it still justifies even more why I’m staying on desipramine! Besides, I’ll bet PTX3 isn’t the whole story anyway. Just an interesting small piece of the puzzle.

Just as a side note: Wouldn’t we all just be totally shocked, though, if the ultimate cause or “trigger” of MS was found to be simple food poisoning at some point in our lives? Salmonella or E coli? And the resulting mutations therefrom?

Anyway, is anyone in MS specifically researching PTX3, its genes, and correlation(s) to MS pathogenesis? Dr. David Hafler, perhaps? Maybe Dr. Moses Rodriguez and his team (with their research on aptamers and proteins) may run across PTX3, also. I see, though, once again, my Netherlands co-horts are on my same wavelength. (Should I move to the Netherlands? HAH!)

I also found where PTX3 is involved with growth factors, too.

If PTX3 is a part of regulation of apoptosis and the innate (i.e. dummie) immune system, then just what IS going on with PTX3 in MS? I’d love to know what the levels of PTX3 are doing at any given time during the course of MS. During a fierce MS exacerbation, what is PTX3 doing? Is it high, or low? Does it do its job, or is it creating havoc? Over-activated, under-activated? Dysfunctional? Triggered too early or too late? Is it mopping up the cells it should or the ones it shouldn’t? Or is it directly involved at all? PTX3 is easily tested, etc. in a patient, but the monitoring of it would most likely have to be fairly close. Not just every six months or so.

Is there some sort of impairment in the PTX3 gene in MS? What role does PTX3 play in MS? Or should I say in certain “patterns” of MS? Is the “timing” of activation off somehow? Or, what if IL1b and TNFa are attempting to get PTX3 to activate and it doesn’t. What then? And is that possibly why desipramine’s actions of inhibiting and/or regulating some of the cytokines’ expression, (which in turn interrelate and/or activate PTX3), help in MS? We know from previous research that desipramine shows indication of being a mild gene therapy, also (e.g. nogo, mitochondria discussions, etc.) Exactly how and to what extent, though?

Just how integral a part does PTX3 (or its possible defective genetic components) play in MS after all? At the very least, I myself believe that monitoring PTX3 in MS can be utilized as a “marker”.

Lots of questions, no answers. As always, my personal comments are highlighted in blue below.

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Ok….here’s what I’ve found:

Number one: The genes associated with PTX3 have been isolated. I’m not certain, but has anyone (Dr. Hafler maybe) determined any PTX3 gene abnormalities in MS patients? I’ve pulled this information out of the middle of the following article. The genes are:

Pentraxin 3 (PTX3) is the first long pentraxin identified. Long pentraxins consist of a C-terminal pentraxin domain, which has sequence similarity to C-reactive protein (CRP) and serum amyloid P (SAP) component (the classic short pentraxins), and of an unrelated N-terminal portion. PTX3 is made by diverse cell types, most prominently endothelial cells, macrophages and dendritic cells, in response to primary inflammatory signals (e.g. interleukin-1 (IL-1), tumour necrosis factor (TNF), lipopolysaccharide (LPS)). It binds diverse ligands, including microbial moieties, C1q and apoptotic cells. Evidence suggests that PTX3 plays a role in the regulation of innate resistance to pathogens, inflammatory reactions, possibly clearance of self-components and female fertility.

Publication Types:
· Review
· Review, Tutorial

PMID: 12763682 [PubMed - indexed for MEDLINE]

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This next article shows where the Netherlands are on board with this, also. We already obviously know this next thing, but I just found it odd that it’s the Netherlands again who appear to be leading the way in this research, also.

Eur J Immunol. 2003 Feb;33(2):465-73.

Biochemical and functional characterization of the interaction between pentraxin 3 and C1q.

Pentraxin 3 (PTX3) is a recently characterized member of the pentraxin family of acute-phase proteins produced during inflammation. Classical short pentraxins, C-reactive protein, and serum amyloid P component can bind to C1q and thereby activate the classical complement pathway. Since PTX3 can also bind C1q, the present study was designed to define the interaction between PTX3 and C1q and to examine the functional consequences of this interaction. A dose-dependent binding of both C1q and the C1 complex to PTX3 was observed. Experiments with recombinant globular head domains of human C1q A, B, and C chains indicated that C1q interacts with PTX3 via its globular head region. Binding of C1q to immobilized PTX3 induced activation of the classical complement pathway as assessed by C4 deposition. Furthermore, PTX3 enhanced C1q binding and complement activation on apoptotic cells. However, in the fluid-phase, pre-incubation of PTX3 with C1q resulted in inhibition of complement activation by blocking the interaction of C1q with immunoglobulins. These results indicate that PTX3 can both inhibit and activate the classical complement pathway by binding C1q, depending on the way it is presented. PTX3 may therefore be involved in the regulation of the innate immune response.

PMID: 12645945 [PubMed - indexed for MEDLINE

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I veered off course here for a second about C1q, but I was curious. All I can say is “very interesting”……….

Immunopharmacology. 2000 Aug;49(1-2):159-70.
Related Articles, Links

C1q: structure, function, and receptors.

Kishore U, Reid KB.

Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK.

C1q is the first subcomponent of the C1 complex of the classical pathway of complement activation. Several functions have been assigned to C1q, which include antibody-dependent and independent immune functions, and are considered to be mediated by C1q receptors present on the effector cell surface. There remains some uncertainty about the identities of the receptors that mediate C1q functions. Some of the previously described C1q receptor molecules, such as gC1qR and cC1qR, now appear to have less of a role in C1q functions than in functions unrelated to C1q. The problem of identifying receptor proteins with complementary binding sites for C1q has been compounded by the highly charged nature of the different domains in C1q. Although newer candidate receptors like C1qR(p) and CR1 have emerged, full analysis of the C1q-C1q receptor interactions is still at an early stage. In view of the diverse functions that C1q is considered to perform, it has been speculated that several C1q-binding proteins may act in concert, as a C1q receptor complex, to bring about C1q mediated functions. Some major advances have been made in last few years. Experiments with gene targeted homozygous C1q-deficient mice have suggested a role for C1q in modulation of the humoral immune response, and also in protection against development of autoimmunity. The recently described crystal structure of Acrp-30, which is a serum protein secreted from adipocytes, has revealed a new C1q/TNF superfamily of proteins. Although the members of this superfamily may have diverse functions, there may be a common theme in their phylogeny and modular organisation of their distinctive globular domains.

The complement system comprises a strong defense against various pathogens and is a major component of our innate immune system. While earlier studies have established a crucial role of complement in recognition, opsonization and enhanced phagocytosis of microorganisms by professional phagocytes such as polymorphonuclear leukocytes and macrophages, recent studies delineate an additional role of complement in initiation and maintenance of the acquired immune response. In addition, it seems that opsonization of apoptotic cells by complement may lead to polarization of the response of professional antigen-presenting cells to a more inflammatory or tolerogenic response. The present review summarizes these different contributions of complement to the shaping of the immune balance. Copyright 2004 S. Karger AG, Basel

Publication Types:
· Review
· Review, Tutorial

PMID: 15218334 [PubMed - indexed for MEDLINE]

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Now with this next publication, we are about to come full circle again with neurotransmitters, neurotrophins, etc. etc. Here is also where we can integrate desipramine back in. Anyway, the below is more research being done by the Netherlands. It will be interesting to see what they find out. This project doesn’t end until 2006:

Project: The Ptx homeobox gene cascade and dysfunctions of the midbrain dopamine systems

Abstract
The dopamine (DA) neurons of the midbrain are key in the control of movement and emotion-related behaviors. Dysfunctions in these systems are implicated in neurological and psychiatric disorders. Molecular mechanisms essential to the appropriate functioning of the midbrain DA (mDA) neurons operate at the level of development, regulation and neuronal maintenance. We have identified several transcription factors and their genetic interactions in mDA neurons. Amongst these factors, the Ptx3 gene is an essential key to these molecular mechanisms. Brain expression of the Ptx3 gene is exclusive to mDA neurons. The gene is induced during terminal differentiation of these neurons, and remains expressed in mature mDA neurons. Another, earlier expressed homeobox genen, Lmx1b, is required for the induction of Ptx3 and for mDA survival during differentiation, but not for TH induction, as we have derived from the analyses of multiple knock-out mice (PNAS 94(1997)13305, PNAS,95(1998)4013, Nature Neurosci. 3(2000)337). We have recently identified a mutant mouse strain deficient in Ptx3 expression, Ptx3(def). This mouse strain displays marked abnormalities in the anatomical localization of mDA neurons and their projections, which suggests that Ptx3 is involved in establishment of appropriate connectivity of mDA neurons. The overall aim of this project is to establish the function of the Ptx3 gene in the cellular and functional integrity of mDA systems. To reach this aim, the dysfunctions of Ptx3-deficient mDA systems will be characterized at the behavioural, pharmacological and neurochemical level. The molecular mechanism underlying the dysfunctions will be determined.

Period
01/2002 - 09/2006

Related organisations

Financier: NWO Council for Earth and Life Sciences
Secretariat: Department of Pharmacology and Anatomy (UU)
Related persons

Parkinson’s disease (PD) is the second major neurodegenerative disease that affects more than 2% of the population above 65 years of age. It is characterised by the selective degeneration of substantia nigra neurons that use dopamine as neurotransmitter. Current management of PD mainly includes symptomatic treatment with L-Dopa. However, the effectiveness of this therapy decreases when the disease progresses. A second approach, restoring dopaminergic activation of the striatum by transplanting dopaminergic neurons derived from human foetuses into the striatum of PD patients, has shown a remarkable ability to ameliorate the symptoms. Besides by medical-ethical concerns, wide clinical application of this grafting approach is hampered by huge practical and logistical problems (e.g. 6-8 foetuses are required for the treatment of one PD patient). A promising alternative as a source for transplantable dopaminergic neurons are stem cells. Pluripotent stem cells (e.g. embryonic stem cells) are characterised by an unlimited self-renewal capacity and the ability to generate a fully differentiated daughter cell of any kind (depending on the induction conditions). Recent literature has provided evidence for the remarkable plasticity of multipotent hematopoietic stem cells in bone marrow to transdifferentiate into cells of other tissues, including nervous tissue. This attractive alternative source may be of considerable interest for autologous cell replacement therapies of neurodegenerative disorders such as PD. My project is part of the recently established multidisciplinary Groningen Stemcell Cluster (GSSC). The specific focus of my project will be to induce efficient pathways leading to specific dopaminergic neuronal differentiation of bone marrow- (and, for comparison, brain-) derived neural stem cells of mice and in a later stage of humans (in collaboration with dr. G. de Haan and drs. A. Wiersema, dept. Stem Cell Biology). The in-vitro differentiation induction will either be initiated by manipulating the culture conditions (e.g. supplementing various defined cocktails of growth factors, cytokines and induction agents) or by transient gene transfection (Nucleofector) of transcription factors (such as Nurr1, Ptx3, etc.) proven to induce dopaminergic lineage development during embryogenesis. The stem cell derived dopaminergic neurons will be characterized by their specific protein expression profile as well as at a functional level with electrophysiology. The restorative capacity of the stem cell derived dopaminergic neurons will be tested in rodent models of PD (in collaboration with prof. Staal; dept of Neurosurgery). The general applicability of our differentiation induction strategies for neural stem cells will eventually be tested also for other neural cell types, e.g. oligodendrocytes as potential cell grafts for multiple sclerosis (MS).

Last modified:
December 15, 2003 13:33

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The following is sort of a “loose” connection at this point, but the majority of us women with MS complain about how our symptoms increase drastically just before menstruation. I just found this interesting how PTX3 is so closely intertwined with fertility and the menstrual cycle. Although, the paradox is that in MS, fertility isn’t directly impaired and shows no direct connection. So….again, just what is PTX3 doing in MS?

Cytokine-induced gene expression at the crossroads of innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14.

Wisniewski HG, Vilcek J.

Department of Microbiology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. wisnih01@med.nyu.edu

Two cytokine-inducible gene products, important in inflammation and infection, also play essential roles in female fertility. One of these is the product of tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6), alternatively termed TNFAIP6 (for TNF-alpha-induced protein 6), originally cloned from diploid human fibroblasts stimulated with TNF. The second is pentraxin 3 (PTX3), also termed TSG-14, originally isolated from TNF-stimulated human fibroblasts and from interleukin-1 (IL-1)-stimulated vascular endothelial cells. TSG-6, which specifically binds to hyaluronan (HA) and to inter-alpha-inhibitor (I alpha I), shows potent anti-inflammatory activity in acute and chronic inflammation, notably in several models of autoimmune arthritis. PTX3 was shown to play an important role in resistance to fungal infection with Aspergillus fumigatus. Both TSG-6 and PTX3 are synthesized in the ovary prior to ovulation, where they become components of an expanding viscoelastic matrix that surrounds the oocyte before its release from the follicle at the ovarian surface. Female mice with a targeted disruption of either the TSG-6 or PTX3 gene show severe defects in fertility.

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